Alnylam Pharmaceuticals has been saying for a while that it needs hard data from clinical trials to prove its skeptics wrong, and today it’s coming out with an early hint of effectiveness with its RNA interference-based treatment for lowering cholesterol.
Cambridge, MA-based Alnylam (NASDAQ: ALNY) is announcing today that it has gotten some encouraging results from a study of 20 patients who got a single shot of Alnylam’s experimental drug called ALN-PCS. This drug, designed to block the activity of a protein known as PCSK9, was able to reduce the protein by an average of 60 percent after four days when given at the highest of five doses studied. That knockdown of the specific protein translated into an average drop of 39 percent in low-density lipoprotein, the so-called “bad” form of cholesterol that clogs arteries and is known to raise people’s risk of heart attack, stroke and death.
The new drug was well-tolerated at a variety of doses, and no one has dropped out of the study because of side effects, although a mild rash was observed in patients on the treatment, the company said. The study is still ongoing, and Alnylam plans to continue examining the safety of higher doses, but the company is communicating the progress before it’s all wrapped up. Preliminary data is being presented today at the Brigham & Women’s Hospital in Boston, and more details are expected to be presented in the first half of 2012, Alnylam said. The company also plans to discuss the results in more detail on a conference call with investors today at 8:30 am Eastern time.
The data is still from the first of three phases of clinical trials normally required for FDA approval, so this drug still has years of rigorous studies to complete if it is ever going to become a new treatment for lowering cholesterol. But the market for cholesterol-lowering drugs was worth $36.4 billion worldwide last year, according to research firm IMS Health, largely because of the huge success of statin drugs. While many of those drugs are losing patents and facing cheap generic rivals, many big biotech and pharma companies (including Amgen and Sanofi) are focusing on a promising new molecular target in PCSK9, which Robert Langreth of Bloomberg News described in a November feature. Carlsbad, CA-based Isis Pharmaceuticals (NASDAQ: ISIS) also has an anti-PCSK9 product in preclinical development with Bristol-Myers Squibb.
Alnylam is wagering that while other companies are focusing on hitting this protein with genetically engineered antibodies, it will have an effective option that works through RNA interference, which specifically silences the RNA that enables the body to make the PCSK9 protein. If Alnylam can continue to show intriguing data from clinical trials (like it did last fall for a rare condition called TTR amyloidosis), it could help revive some of the enthusiasm for RNAi. Excitement for the technique once ran high because of its new ability to molecular targets that have been considered “undruggable” in the past, but enthusiasm has waned in the past couple years as big companies like Roche and Merck have curtailed their RNAi drug development activities.
The data so far for Alnylam’s PCSK9 program is still quite preliminary. Researchers randomly assigned 20 patients withslightly elevated LDL cholesterol (greater than 116 grams/deciliter of blood) to get either one of five different doses or a placebo. The higher the doses went, the better the drug appeared to be at reducing PCSK9 in the bloodstream, as well as LDL. PCSK9 is thought by scientists to be a key to lowering cholesterol, because it makes a protein that interferes with the liver’s ability to get rid of excess cholesterol. Scientists have become increasingly convinced after finding certain individuals with mutant forms of PCSK9 who have extremely low cholesterol.
The study didn’t follow up with patients for an extended period of time, but the anti-PCSK9 effect appeared to be durable enough for Alnylam to consider once-monthly injections for future studies. Importantly to Alnylam, this study used its second-generation lipid-nanoparticle delivery technology, which it intends to use widely in its pipeline of experimental drugs, and which is supposed to be far more potent than other technologies it has used in previous clinical trials.
Lots of questions will surely pop up based on the intriguing early finding. What will be the ideal dose of such an RNAi drug? How does the data compare with cheap generic statins, or anti-PCSK9 antibody drugs in development? How long does the RNAi treatment really last? Does the quick lowering of PCSK9 really translate into extra benefit in lowering of heart attack risk? And how widely might such a drug be used—would it be for large numbers of patients, or only those with extremely high cholesterol that doesn’t respond to statin therapy?
I expect to gather more material on this finding today and will update if necessary.
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